Neurological brain diseases progress by the death of nerve cells for a short or long time and result in fatal loss of brain function. Stroke is one of the cerebrovascular diseases most frequently generated. Because cranial nerve disorders in patients in the vigorous age group from the forties to fifties have remarkably increased, it is pointed out as not only an individual issue but also a national issue.
There are largely two kinds of stroke: cerebral infarction and cerebral hemorrhage. Cerebral infarction results from necrosis of brain tissue caused by a blockage of blood supply to brain tissue brought on by thrombus and so forth. Cerebral hemorrhage, on the other hand, results from loss of blood due to ruptured blood vessels in the brain. Although the pathogeneses of cerebral infarction and cerebral hemorrhage are different, their symptoms are often similar.
The standard method for treating the acute period of infarction is currently thrombolysis. The time period before starting treatment and after onset of cerebral infarction is very important, and it is known that the patient's functional status can be improved when a thrombolytic agent is administrated within 3 hours after onset of cerebral infarction.
The cause of brain cell necrosis due to ischemia has been elucidated by many researchers, and the main pathway is suggested as excitable toxicity by excessive neurotransmitter, oxidative toxicity by stress, zinc toxicity, apoptosis and so forth.
Glutamate, which is one of the excitable toxic substances, is an excitable neurotransmitter of the central nervous system, and it reacts with NMDA (N-methyl-D-aspartate) receptor. Death of nerve cells is induced when glutamate is overproduced by ischemia. It is recently reported that these excitable toxicities may be the main mechanism of nerve cell's death by ischemic stroke as well as epilepsy. If the supply of oxygen-glucose to nervous tissue after ischemia is reduced, glutamate which is an excitable neurotransmitter, is accumulated in the junction between neurons. And then, nerve cell's death by excessive activity of NMDA glutamate receptor mainly occurs. Therefore, nerve cell's death by ischemic stroke can be suppressed by using antagonist of NMDA glutamate receptor.
Free radicals are also one of the main mechanisms of nerve cell death. An increase of free radicals by ischemia and others in nerve cells induces destruction of membrane lipid by lipid peroxidation, damage of nucleic acid by oxygen radicals, denaturation of protein and the like. This results in fatal damage to essential factors for cell survival. Many researchers have reported that ischemia leads to increases of active oxygen in the brain, reactive oxygen species in Parkinson's disease, Huntington's disease and Alzheimer's disease, catalase (a radical-scavenging enzyme), activity of Cu/Zn superoxide dismutase (SOD) and Fe2+.
As mentioned above, although many mechanisms are revealed to treat cranial nerve disorders, development of new drugs is delayed because of problems about efficacy and toxicity.
The present inventors found out that natural substances are released from living Eisenia Andrei and Eisenia fetida given electrostimulation while we studied them from folk remedies long used in the Orient. And we discovered that specific compounds of these substances show the valid protection of cranial nerves. Many derivative compounds including new compounds isolated from natural products were synthesized based on this discovery. It was learned that quinazoline-2,4-dione derivative compound of formula (I) and a salt thereof have a superior effect on protecting the activity of nerve cells, and we perfected the present invention.